Department of Medical Genetics and Biochemistry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
Department of Legal Medicine, Shimane University School of Medicine, Enya, Izumo, Japan.
Sci Rep. 2019 Sep 20;9(1):13660. doi: 10.1038/s41598-019-49935-y.
Genetic variants, such as single nucleotide polymorphisms (SNPs), in the deoxyribonuclease I (DNase I) gene which remarkably reduce or abolish the activity are assumed to be substantially responsible for the genetic backgrounds determining susceptibility to autoimmune dysfunction. Here, we evaluated many genetic variants, including missense and nonsense SNPs, and indel (inframe) variants in the gene, potentially implicated in autoimmune diseases as functional variants resulting in altered activity levels. Eighteen missense and 7 nonsense SNPs, and 9 indel (inframe) variants were found to result in loss of function and disappearance of DNase I activity. Furthermore, considering the positions in the DNase I protein corresponding to the various nonsense SNPs, all of the other nonsense SNPs and frameshift variants registered in the Ensembl database ( https://asia.ensembl.org ) appear likely to exert a pathogenetic effect through loss of the activity. Accordingly, a total of 60 genetic variants in the DNase 1 gene (DNASE1) inducing abolishment or marked reduction of the DNase I activity could be identified as genetic risk factors for autoimmunity, irrespective of how sparsely they were distributed in the population. It was noteworthy that SNP p.Gln244Arg, reportedly associated with autoimmunity and reducing the activity to about half of that of the wild type, and SNP p.Arg107Gly, abolishing the activity completely, were distributed worldwide and in African populations at the polymorphic level, respectively. On the other hand, with regard to copy number variations in DNASE1 where loss of copy leads to a reduction of the in vivo enzyme activity, only 2 diploid copy numbers were distributed in Japanese and German populations, demonstrating no loss of copy. These exhaustive data for genetic variants in DNASE1 resulting in loss or marked reduction of the DNase I activity are highly informative when considering genetic predisposition leading to autoimmune dysfunction.
脱氧核糖核酸酶 I（DNase I）基因中的遗传变异，如单核苷酸多态性（SNP），显著降低或消除其活性，被认为是决定自身免疫功能障碍易感性的遗传背景的主要因素。在这里，我们评估了许多基因变异，包括错义和无义 SNP，以及可能与自身免疫性疾病相关的基因中的插入缺失（INDEL）（框架内）变异，这些变异可能导致活性水平改变。发现 18 个错义 SNP、7 个无义 SNP 和 9 个 INDEL（框架内）变异导致功能丧失和 DNase I 活性消失。此外，考虑到 DNase I 蛋白中对应于各种无义 SNP 的位置，Ensembl 数据库（https://asia.ensembl.org）中注册的所有其他无义 SNP 和移码变异似乎都可能通过丧失活性产生致病作用。因此，在 DNase 1 基因（DNASE1）中总共可以鉴定出 60 个导致 DNase I 活性完全或显著降低的遗传变异，这些变异可作为自身免疫的遗传风险因素，无论它们在人群中的分布有多稀疏。值得注意的是，据报道与自身免疫相关并将活性降低到野生型的大约一半的 SNP p.Gln244Arg 和完全消除活性的 SNP p.Arg107Gly 分别在世界范围内和非洲人群中以多态性水平分布。另一方面，对于导致体内酶活性降低的 DNASE1 中的拷贝数变异，只有 2 个二倍体拷贝数在日本和德国人群中分布，没有拷贝数丢失。考虑到导致自身免疫功能障碍的遗传易感性，这些导致 DNase I 活性丧失或显著降低的 DNASE1 遗传变异的详尽数据非常有意义。
